Preparation method and application of nafamostat intermediate

Abstract

The invention belongs to the field of preparation of drug intermediates, and particularly relates to a preparation method and application of a nafamostat intermediate. The preparation method comprises the following steps: in a solvent, reacting p-guanidinobenzoic acid hydrochloride with an acylation reagent in the presence of a catalyst to obtain the nafamostat intermediate p-guanidinobenzoyl chloride hydrochloride, wherein the acylation reagent is one or more of oxalyl chloride, thionyl chloride and phosphorus oxychloride. The nafamostat or nafamostat pharmaceutically acceptable salt prepared from the intermediate is low in cost, simple to operate and short in production period.

Description

Technical Field

[0001] The present invention belongs to the field of drug preparation, and relates to a preparation method and application of an intermediate of nafamostat mesilate for treating acute pancreatitis. Background Art

[0002] Acute pancreatitis (AP) is one of the common abdominal diseases, mostly seen in young and middle-aged people, with a high morbidity and mortality rate of about 30 - 50%. There are still many problems unsolved in the research on the etiology, pathogenesis, clinical prevention and treatment of acute pancreatitis. At present, it is generally believed that the unlimited activation of trypsin locally in the lesion leading to the autodigestion of pancreatic tissue is an important factor for the deterioration of the condition of acute pancreatitis. Even a small amount of protease in the pancreatic juice of patients, once activated, becomes the enzyme with the strongest digestive effect. At the same time, it plays a role in initiating the activation cascade of various enzymes, enabling multiple pancreatic digestive enzymes to be activated simultaneously and synergistically to carry out a powerful autodigestion of the pancreas. Therefore, it is particularly important to develop drugs that inhibit the activity of trypsin.

[0003] Nafamostat mesilate was first developed by Torii Pharmaceutical Co., Ltd. in Japan and was launched in Japan in October 1986, mainly used for the treatment of acute pancreatitis. In the early process of preparing nafamostat, 6-amidino-2-naphthol methanesulfonate and p-guanidinobenzoic acid hydrochloride were used as raw materials, and DCC was used as a condensation reaction catalyst. The by-product 1,3-dicyclohexylurea (DCU) was produced during the reaction. The by-product is a viscous solid, difficult to filter, and there is also a carbonate intermediate which is a viscous solid, making production difficult, with a high impurity content, requiring multiple refinements, consuming a large amount of solvent, and having a high production cost. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a preparation method of a nafamostat intermediate, and the cost of nafamostat or a pharmaceutically acceptable salt thereof prepared through this intermediate is low, the operation is simple, and the production cycle is short.

[0005] The technical solution provided by the present invention is as follows: A preparation method of a nafamostat intermediate, comprising the following steps: in a solvent, p-guanidinobenzoic acid hydrochloride reacts with an acylating agent in the presence of a catalyst to obtain the nafamostat intermediate p-guanidinobenzoyl chloride hydrochloride; wherein, the acylating agent is one or more of oxalyl chloride, thionyl chloride, and phosphorus oxychloride.

[0006]

[0007] Further, the catalyst is N,N-dimethylformamide, N,N-dimethylaniline, or pyridine.

[0008] Further, the solvent is one or more of dichloromethane, ethyl acetate, pyridine, and isopropyl acetate.

[0009] Furthermore, the molar ratio of guanidinobenzoic acid hydrochloride to the acylating agent is 1:1 to 2.

[0010] Furthermore, after adding the catalyst to the mixed solution of guanidinobenzoic acid hydrochloride and the acylating agent, the temperature is raised to 30 - 40°C, and the mixture is kept warm and stirred for 4 - 6 hours.

[0011] Furthermore, after the reaction of guanidinobenzoic acid hydrochloride with the acylating agent is completed, the temperature is lowered to 0 ± 5°C by stirring, and the mixture is kept warm for crystallization for 0.5 - 1.5 hours, then filtered by suction, and after drying, the intermediate of nafamostat, guanidinobenzoyl chloride hydrochloride, is obtained.

[0012] The present invention also provides an intermediate of nafamostat, which is prepared by the above - mentioned preparation method.

[0013] The present invention provides the application of the above - mentioned preparation method or the above - mentioned intermediate of nafamostat in the preparation of nafamostat or a pharmaceutically acceptable salt of nafamostat. The intermediate of nafamostat and 6 - amidino - 2 - naphthol methanesulfonate are reacted in a basic organic solvent to prepare nafamostat hydrochloride.

[0014]

[0015] Furthermore, the pharmaceutically acceptable salt of nafamostat includes nafamostat mesylate.

[0016] Furthermore, the basic organic solvent is pyridine.

[0017] The method for preparing nafamostat mesylate from the intermediate of the present invention includes the following steps:

[0018] Firstly, guanidinobenzoic acid hydrochloride is prepared into guanidinobenzoyl chloride hydrochloride through oxalyl chloride; then, this intermediate and 6 - amidino - 2 - naphthol methanesulfonate are reacted in a basic organic solvent to prepare nafamostat hydrochloride; finally, the reaction is carried out with methanesulfonic acid in an organic solvent, and after purification, nafamostat mesylate is obtained.

[0019] Beneficial effects

[0020] Nafamostat mesilate was first prepared by passing HCl gas into anhydrous methanol or anhydrous ethanol until saturated with 6-cyano-2-naphthol, adding 6-cyano-2-naphthol to undergo the Pinner reaction to obtain 6-hydroxy-2-naphthimidate methyl ester hydrochloride, and then passing ammonia gas for ammonolysis reaction to obtain 6-amidino-2-naphthol. 6-amidino-2-naphthol was successively reacted with sodium bicarbonate and methanesulfonic acid to be converted into 6-amidino-2-naphthol methanesulfonate; then 6-amidino-2-naphthol methanesulfonate, p-guanidinobenzoic acid hydrochloride, and N,N'-dicyclohexylcarbodiimide (DCC) were reacted in pyridine. The resulting precipitate was filtered, and the filtrate was reacted with sodium bicarbonate solution. The resulting precipitate was filtered to obtain nafamostat carbonate, and then converted into nafamostat mesilate by salification with methanesulfonic acid. By-products 1,3-dicyclohexylurea (DCU), which is a viscous solid, are produced during this reaction process. When filtering and removing it, there are problems with difficult filtration. At the same time, because it is a viscous product, it is easy to cause the target product to be wrapped in this DCU, reducing the yield, and the purity of the target product cannot be improved; during the preparation of carbonate, the prepared nafamostat carbonate reactant is also viscous and not in a good solid state. Therefore, it is difficult to carry out sufficient washing to achieve the purpose of purification. At the same time, filtration is difficult, and the stability is poor, and the product purity cannot be guaranteed. The production cycle is long, and the operation is complex; moreover, the dried carbonate is hard and caked, and it needs to be pulverized before the next step of salification with methanesulfonic acid. Therefore, during the reaction, there are easily problems such as incomplete reaction conversion and more impurities in the product. Due to the high impurity content and deep coloring in the product, multiple refinements are required, consuming a large amount of solvents, increasing the production cost, reducing the product yield, and causing relatively serious environmental pollution.

[0021] In the present invention, p-guanidinobenzoyl chloride hydrochloride is used as an intermediate, and nafamostat mesilate is prepared through a total of two-step reactions, which simplifies the existing technology, improves the yield and purity. On the other hand, it reduces the use of production equipment, shortens the production cycle, and reduces the cost, making it more suitable for industrial production. The nafamostat mesilate prepared in the present invention can be used as a protease inhibitor for the treatment of pancreatitis.

[0022] The nafamostat hydrochloride prepared in the present invention can be used not only for the preparation of nafamostat mesilate but also for the preparation of other acid radical salts of nafamostat. Description of the Drawings

[0023] Figure 1 It is the related substance spectrum of p-guanidinobenzoyl chloride hydrochloride;

[0024] Figure 2 It is the 1H NMR spectrum of p-guanidinobenzoyl chloride hydrochloride methanol derivatization;

[0025] Figure 3The MS spectrum of the methanol derivative of guanidinobenzoyl chloride hydrochloride. Detailed implementation mode

[0026] The content of the present invention will be further described in detail below by way of examples. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples only. Modifications made by corresponding substitutions or changes according to common general knowledge and customary means in the art without departing from the above-mentioned technical premise of the present invention are all included in the scope of the present invention.

[0027] Example 1

[0028] In a 1L reaction flask, 28 g of guanidinobenzoic acid hydrochloride was added to 300 g of dichloromethane. Stirring was started, a catalytic amount of DMF was added, and 20 g of oxalyl chloride was added dropwise. After the addition was completed, the temperature was raised to 30 - 40 °C, and the mixture was stirred at a constant temperature for 4 - 6 hours. After the reaction was completed, the mixture was stirred and cooled to 0 ± 5 °C, and crystallized at a constant temperature for 1 hour. After filtration and drying, 30 g of guanidinobenzoyl chloride hydrochloride was obtained, with a yield of 98.7%.

[0029] Example 2

[0030] In a 1L reaction flask, 20 g of guanidinobenzoic acid hydrochloride was added to 100 g of ethyl acetate. Stirring was started, a catalytic amount of DMF was added, and 18 g of oxalyl chloride was added dropwise. After the addition was completed, the temperature was raised to 40 - 60 °C, and the mixture was stirred at a constant temperature for 4 - 6 hours. After the reaction was completed, the mixture was stirred and cooled to 0 ± 5 °C, and crystallized at a constant temperature for 1 hour. After filtration and drying, 20 g of guanidinobenzoyl chloride hydrochloride was obtained, with a yield of 92.2%.

[0031] Example 3

[0032] In a 1L reaction flask, 20 g of guanidinobenzoic acid hydrochloride was added to 100 g of isopropyl acetate. Stirring was started, a catalytic amount of DMF was added, and 23.5 g of oxalyl chloride was added dropwise. After the addition was completed, the temperature was raised to 40 - 60 °C, and the mixture was stirred at a constant temperature for 4 - 6 hours. After the reaction was completed, the mixture was stirred and cooled to 0 ± 5 °C, and crystallized at a constant temperature for 1 hour. After filtration and drying, 21 g of guanidinobenzoyl chloride hydrochloride was obtained, with a yield of 96.8%.

[0033] Example 4

[0034] Add 190.6 kg of pyridine to the reaction flask, stir and cool down to 0 °C, add 40.0 g of 6-amidino-2-naphthol methanesulfonate and 60.0 g of 4-guanidinobenzoyl chloride hydrochloride, stir at room temperature for 10 to 12 hours; carry out suction filtration, add the filter cake to 150 ml of methanol, heat up to 50 ± 5 °C, add 40.1 g of methanesulfonic acid, keep warm and stir for 0.5 hour, carry out suction filtration to obtain the crude product of nafamostat mesilate; add 100 g of water and 160 g of acetone to the crude product, heat to dissolve it clearly, then add activated carbon, after filtration, adjust the pH to 2 with methanesulfonic acid, cool down, crystallize, to obtain 35.2 g of nafamostat mesilate, with an overall yield of 46% and a product purity of 99.8%.

Claims

1. A preparation method of nafamostat intermediate, characterized in that, It includes the following steps: in a solvent, react guanidinobenzoic acid hydrochloride with an acylating agent in the presence of a catalyst to obtain the nafamostat intermediate guanidinobenzoyl chloride hydrochloride; wherein, the acylating agent is one or more of oxalyl chloride, thionyl chloride, and phosphorus oxychloride.

2. The preparation method of the nafamostat intermediate according to claim 1, wherein The catalyst is N,N-dimethylformamide, N,N-dimethylaniline, or pyridine.

3. The preparation method of the nafamostat intermediate according to claim 1, characterized in that, The solvent is one or more of dichloromethane, ethyl acetate, pyridine, and isopropyl acetate.

4. The preparation method of the nafamostat intermediate according to claim 1, characterized in that, The molar ratio of guanidinobenzoic acid hydrochloride to the acylating agent is 1:1 to 2.

5. The preparation method of the nafamostat intermediate according to claim 1, wherein, After adding the catalyst to the mixed solution of guanidinobenzoic acid hydrochloride and the acylating agent, heat up to 30 to 40 °C and keep stirring for 4 to 6 hours.

6. The preparation method of the nafamostat intermediate according to claim 1, wherein, After the reaction of guanidinobenzoic acid hydrochloride and the acylating agent is completed, stir and cool down to 0 ± 5 °C, keep the temperature for crystallization for 0.5 to 1.5 hours, filter by suction, and obtain the nafamostat intermediate guanidinobenzoyl chloride hydrochloride after drying.

7. A nafamostat intermediate, characterized in that, It is prepared by the preparation method described in any one of claims 1 to 6.

8. Use of the preparation method according to any one of claims 1-6 or the nafamostat intermediate according to claim 7 in the preparation of nafamostat or a pharmaceutically acceptable salt thereof, characterized in that, React the nafamostat intermediate with 6-amidino-2-naphthol methanesulfonate in a basic organic solvent to prepare nafamostat hydrochloride.

9. The application according to claim 8, wherein The pharmaceutically acceptable salts of nafamostat include nafamostat mesylate.

10. The application according to claim 8, characterized in that, The basic organic solvent is pyridine.

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